The env gene of the primate lentiviruses, HIV and SIV, is a major determinant of several in vitro viral properties and an important target of anti-viral immune responses. HIV-1, the main viral type associated with AIDS throughout the world, does not efficiently infect macaques. However, chimeric viruses, constructed by replacing genes of the pathogenic clone SIV mac239 with genes from HIV-1, establish persistent infection and cause fatal simian AIDS in macaques. Such chimeras, designated SHIVs, provide a means for in vitro analysis of env gene properties of HIV-1 subtype-B as well as other subtypes. These properties include cell tropism, cytopathicity, and sensitivity to neutralizing antibodies. Recent studies have shown that the second receptor (i.e., co-receptor or fusion receptor) for primate lentiviruses consists of several cell surface proteins related to members of the chemokine receptor family. Accordingly, the interaction of the env gene in pathogenesis can be investigated by analyzing SHIV recombinant viruses in rhesus macaques. Three Specific Aims are proposed: (I) to assess the significance of env gene sequence changes in "adapted" SHIV for infection and pathogenesis in rhesus macaques, (ii) to examine the role of cell surface co-receptors in SHIV infection and pathogenesis in macaques, and (iii) to analyze immune system dysfunction in macaques infected with pathogenic SHIV. Through the mechanism of Interactive Research Project Grants (IRPG) the collaborative research of P. Luciw (University of California, Davis) and C. Cheng-Mayer (Aaron Diamond AIDS Research Center, NY) will develop critically important synergies between in vitro and in vivo analysis of HIV-1 env functions. Elucidation of the molecular basis of adaptation of HIV-1 env to the non-human primate host may reveal the significance of env gene properties for viral persistence, immunopathogenesis, and transmission. Novel SHIV clones utilizing various co-receptors will be essential for evaluation of anti-viral vaccines and novel anti-viral inhibitors which are aimed at blocking virion entry into cells. Taken together, these two IRPGs meet the Research Objectives of the Public Announcement (PA-96-072) entitled Mechanisms of AIDS Pathogenesis.